3-Nitrohalosalicylanilides

ABSTRACT

3-Nitrohalosalicylanilides having one or more halogen substitutions on the aniline ring which compounds have selective activity against brown bullheads and larvae of sea lamprey as opposed to rainbow trout and also have anti-radiation activity and activity against certain fungi.

United States Patent [1 1 Taborsky Dec. 30, 1975 3-NITROHALOSALICYLANILIDES [75] Inventor: Robert G. Taborsky, Bedford [21] Appl. No.: 730,596

Related U.S. Application Data [63] Continuation-impart of Ser. No. 469,300, July 2, 1965, abandoned, which is a continuation-in-part of Ser. Nos. 325,473, Nov. 21, 1963, abandoned, and Ser. No. 435,686, Feb. 26, 1965, abandoned, each is a continuation-in-part of Ser. No. 56,679, Sept. 19, 1960, abandoned. I

[52] U.S. Cl. 260/559 S; 210/64; 424/59; 424/324 [51] Int. Cl. C07C 103/76 [58] Field of Search 260/559 S [56] References Cited UNITED STATES PATENTS 3,079,297 2/1963 Schraufstatter et al. 260/559 S Strufe et al. 260/559 S Howell et al 424/230 OTHER PUBLICATIONS loffe et al. 1 Zhur. Obshihei Khim. Vol. 29, pp. 2682-2685 (1959, Aug. 1959).

Ioffe et al. 11 Chem. Abst. Vol. 54, Column 10938 (1960).

Primary ExaminerNatalie Trousof Attorney, Agent, or FirmCain and Lobo [57] ABSTRACT 3-Nitrohalosalicylanilides having one or more halogen substitutions on the aniline ring which compounds have selective activity against brown bullheads and larvae of sea lamprey as opposed to rainbow trout and also have anti-radiation activity and activity against certain fungi.

9 Claims, No Drawings 3-NITROHALOSALICYLANILIDES CROSS-REFERENCES TO RELATED APPLICATIONS This application is a continuation-in-part of applicantscopending application Ser. No. 469,300 filed July 2, 1965, now abandoned which was a continuawherein Y is a halogen and n is a positive integer no greater than 5. In another broad form of this invention n is a positive integer no greater than 3.

Corrected tion-in-part of applicants then copending applications, Ser. No. 325,473, filed Nov. 21, 1963, now abandoned and Ser. No. 435,686 filed Feb. 26, 1965, now abandoned, each of which was continuation-in-part application of applicants then copending application, Ser. No. 56,679 filed Sept. 19, 1960, now abandoned.

BACKGROUND OF THE INVENTION 1. Field of Invention This invention relates to new substituted salicylani lides and more particularly to new nitrohalosalicylanilides, to wit 3-nitrohalosalicylanilides, which compounds exhibit new, unobvious and unexpected beneficial and useful characteristics over the 5-nitro-4'- chlorosalicylanilide known to the prior art.

2. Description of the Prior Art The only nitrohalosalicylanilide known to the prior art is 5-nitro-4'-chlorosalicylanilide. The prior art neither discloses nor suggests 3-nitrohalosalicylanilides which applicant has provided and which exhibit and have unobvious and unexpected properties, characteristics and advantages overthe prior art compound, properties, characteristics and advantages which are useful and beneficial and which cannot be obtained or realized by the prior art 5-nitro-4-chlorosalicylanilide and would not be expected or obvious from the said prior art compound.

SUMMARY OF INVENTION DESCRIPTION OF THE PREFERRED EMBODIMENTS Broadly, the new-substituted salicylanilides which are provided by this invention correspond to the following formula:

NO H

-CO-NH 3-nitrohalosalicylanilides embodying this invention may be produced by a number of methods including, for example, reacting 3-nitrosalicoyl chloride with an excess of the halogenated aniline in benzene and recrystallizing or by reacting the acid, the aniline and phosphorous trichloride in benzene:

EXAMPLE I A solution of 25 grams (0.12 mole) of 3-nitrosa1icoyl chloride in 200 milliliters of benzene was added with shaking to 50 grams (0.39 mole) of para-chloroaniline in 150 milliliters of benzene. An immediate yellow precipitate formed which was allowed to stand over night and then vacuum filtered. The solid obtained was washed with small amounts of benzene, air dried, pulverized, and then stirred for 30 minutes in 100 milliliters of 10% hydrochloric acid. The product was then vacuum filtered again, washed well with water, and dried at for 16 hours to give 28.5 grams (78.5% yield) of crude 3-nitro-4-chlorosalicylanilide, having a melting point of 153156C. The crude 3-nitro-4- chlorosalicylanilide was crystallized from 600 milliliters of ethanol to give 23.0 grams of yellow needles in a first crop and additional 3.6 grams by reducing the alcohol filtrate to one-sixth, or a total of 26.6 grams of 3-nitro-4'-chlorosalicylanilide having a melting point of 154156C.

The other 3-nitrohalosalicylanilides provided by this invention, when prepared in accordance with the procedure of this example, were obtained in molar yields of from 71 to 93%.

EXAMPLE 11 Similarly, 5.0 grams (0.025 mole) of 3-nitrosalicoyl chloride were reacted with 9.2 grams (0.083 mole) of parafluoroaniline for 18 hours in benzene to give 3- nitro-4-fiuorosalicylanilide having a melting point of 141 .5-l42 upon crystallization from ethanol.

EXAMPLE 111 Similarly, 5.0 grams (0.025 mole) of 3-nitrosa1icoyl chloride were reacted with 10.6 grams (0.083 mole) of orthochloroaniline in benzene to give 3-nitro-2'- chlorosalicylanilide, having a melting point of 171.5 172.5 upon crystallization from ethanol.

EXAMPLE 1V Similarly, 5.0 grams (0.025 mole) of 3-nitrosa1icoyl chloride were reacted with 10.6 grams (0.083 mole) of 3 metachloroaniline in benzene to give 3-nitro-3'- chlorosalicylanilide, having a melting point of 152.5-153.5 upon crystallization from ethanol.

EXAMPLE V 4 much money, time and effort has been expended in seeking a practical way to eradicate or control the sea lamprey without, however, causing injury or damage to commercially useful fish and other aquatic life and 5 users of the water. Lamprey reproduce by laying their Similarly, 5.0 grams (0.025 mole) of 3-nitrosalicoyl eggs in the streams which feed the lakes, and it has chloride and 14.3 grams (0.083 mole) of parabeen proposed to control the lamprey by killing the bromoaniline were reacted in benzene for 18 hours to larvae, which are hatched from the eggs, in the streams. give 3-nitro-4'-br0mosalicylanilide, having a melting Such larvicides must, of course, be capable of killing point of 158158.5 upon crystallization from ethanol. the larvae, one hundred percent, in reasonable concentrations, in a reasonable time and at a rational cost and EXAMPLE VI have no residual or toxic effect, as used, against human Similarly, 5.0 grams (0.025 mole) of 3-nitrosalicoyl and other animals. Equally important, the difference chloride were reacted with 18.2 grams (0.083 mole) of between the concentrations of the larvicide, which will paraiodoaniline in benzene for 18 hours to give 3-nitrobe completely effective against the sea lamprey larvae 4'-iodosalicylanilide, having a melting point of and which appreciably kill economically valuable fish, 175-178 upon crystallization from ethanol. should be as great as possible, so as to provide the best possible margin of safety between the two concentra- EXAMPLE tions. It is desired therefore to provide more potent and Similarly, 5.0 grams (0.025 mole) of 3-nitrosalicoyl 20 selective sea lamprey larvicides. chloride were reacted with 13.4 grams (0.083 mole) of Sea lamprey live as parasites on beneficial fish and 2,4-dichloroaniline for 18 hours in benzene to give annual losses caused the Great Lakes fishing industry 3-nitro-2', 4'-dichlorosalicylanilide, having a melting by the lamprey have risen above 7.5 million dollars. In point of 241. Lake Superior, alone, the annual trout harvest dropped When 2, 4-,dichloroaniline reacted with the nitrosalfrom 47 million pounds in 1950 to 367,000 in 1961. icoyl chloride, the rate of reaction was slower than with Certain of the above and other nitrohalosalicylanithe monohaloanilines and precipitate did not start to lides have been tested for toxic and selective effect on form until about 1 hour after mixing and did not fill the sea lamprey larvae and Rainbow trout. In making the mixture until several hours later. With the tests, larval sea lamprey (Petromyzon marinus) and monohaloanilines, precipitation occurred immediately fingerling rainbow trout (Salma gairdneri) were exand satisfactory yields were obtained in about 1 hour posed for 24 hours at 12C. in battery jars containing after mixing. varying concentrations in parts per millions of the test As noted above, 3-nitrohalosalicylanilides, embodycompound dissolved in aerated water drawn from Lake ing this invention have and have exhibited, both gener- Huron. Viability was determined at the conclusion of ally and specifically, unexpected and unobvious useful the test period. The effectiveness of the compound and beneficial advantages and results over the 5-nitroagainst sea lamprey larvae was determined on the basis 4-chlorosalicylanilide of the prior art, as well as over of a one hundred percent kill. In contrast, the effectiveother 5-nitrohalosalicylanilides which are not disclosed ness of the compound against trout was determined for nor suggested in the prior art. a concentration which would not kill in excess of 25% Thus, for example, 3-nitro-4'-iodosalicylanilide exof a given population, since a greater kill is not considhibits great and unexpected selectivity as between ered desirable with respect to the economically valubrown bullheads (Ictalurus nebulosus) and rainbow able test fish. Preliminary screening eliminated comtrout (Salmo gairdneri) being 40 times more lethal to pounds requiring a greater than 10 PPM concentration the brown bullheads than to the rainbow trout. Further, in order to produce a 100% kill. The concentrations and even more unobvious and unexpected, 3-nitro-4- necessary to produce these effects vary with the condiiodosalicylanilide exhibits piscicidal activity at low tions under which they are used, but the tests are contemperatures taking, for example, only twice as long to sidered valid for determining usefulness. completely eradicate the aforesaid brown bullheads at The following table indicates the parts per million of 47F as at 70, for equivalent concentration. the respective compounds and mixtures of compounds Neither selective activity nor activity at such low 50 found necessary to produce a total kill (LD in sea tempertures is evidenced by the aforesaid prior art lamprey larvae and a kill not in excess of 25% (LD in 5-nitro-4-chlorosalicylanilide. Rainbow Trout. The activity index expresses the selec 3-nitrohalosalicylanilides provided by this invention tivity of the compound for lamprey larvae at LD to have also been found unexpectedly and unobviously Rainbow Trout at LD as a mathematical ratio of the useful and advantageous as selective larvicides for sea concentrations necessary to produce the respective lamprey. In recent years sea lamprey have caused great lethal effects the larger the activity index the greater damage to commercial fish in the Great Lakes and the selectivity of the compound as a larvicide.

TABLE 11 Larvicidal Trout Activity COMPOUND LD 1.0., Index 3-nitro-2'-chlorosalicylanilide 3.0 7.0 2.33 3nitro3'-chlorosalicylanilide 0.3 0.9 3.0 3-nitro-4'-chlorosalicylaniIide 0.3 0.9 3.0 3 nitro2'-fluorosalicylanilide 3.0 3.0 1.0 3-nitro-3 -fluorosalicylanilidc 0.5 0.9 1.8 3-nitro4'-flu0rosalicylanilide 10.0 10.0 3-nitro-2'-iodosulicylanilide 1.0 3.0 3.0 3-nitro-3'-iodosalicylanilide 0.3 1.0 3.3 3-nitro4'-iodosalicylanilide 0.3 0.7 2.33

TABLE II-continued Larvicidal Trout Activity COMPOUND LD LD, Index 3-nitro-2'-bromosalicylanilide 1.0 1.0 LD 3-nitro-3 '-bromosalicylanilide 0.3 1.0 3.3 3-nitro-4'-bromosalicylanilide 0.3 1.0 3.3 3-nitro-2,5'-dichlorosalicylanilide 0.3 0.9 3.0 3-nitro-3',4'-dichlorosalicylanilide 0.3 0.5 1.6 5-nitro-4'-chlorosalicylanilide 0.5 1.0 2.0

(prior art) As seen in Table II, 3-nitrohalosalicylanilides not only are lethal to sea lamprey larvae but also provide efficient and effective means for controlling sea lamprey because of the unobvious and unexpected effect of 3-nitrohalosalicylanilides in general, and 3-nitro-4'- halosalicylanilides, in particular, in providing a sea lamprey larvicide effective at low concentration and having a wide selectivity range between lethal effectiveness against the sea lamprey larvae and against economically desirable aquatic life, such as trout, vis-avis the prior art 5-nitro-4'-chlorosalicylanilide is shown in Table II above. Note, in particular, that 3-nitro-4'- chlorosalicylanilide is not only effective against the larvae at a concentration 40% lower than the 5-nitro- 4'-chlorosalicylanilide but even so has a 50% greater selectivity than the prior art compound; such higher effectiveness and selectivity is not obvious nor expected from the prior art disclosure.

Further 3-nitro-4-chlorosalicylanilide and S-nitro- 4-chlorosalicylanilide were screened against the fungi, Trichophyton Mentagrophytes, Candida Albicans, Pencillium Luteum and Epidermorphyton Fluccosum by incorporating various concentrations of the two nitrohalosalicylanilides into the media upon which the fungi were grown on glass plates. This was done by inoculating the test organism into a medium composed of a base of plain agar containing the test compound overlaid by a layer of potato dextrose agar.

When so tested 3-nitro-4'-chlorosalicylanilide exhibited unexpected and unobviously greater activity as a fungicide than did the prior art 5'-nitro,4'- chlorosalicylanilide.

Also the 3-nitro-4-chlorosalicylanilides of this invention, as shown by the table below, exhibit unpredictable, marked, unexpected and unobvious greater anti- 1. A 3-nitrohalosalicylanilide having the formula NO OH Yn where Y is a halogen and n is a positive integer no greater than 5.

2. A 3-nitrohalosalicylanilide having the formula 'NO OH where Y is a halogen and n is a postive integer no greater than 3.

3. The 3-nitrohalosalicylanilide according to claim 2 having the formula NO radiation activity than the prior art 5-n1tro-4'- 2 chlorosalicylanilide when tested in accordance with (0 co NH accepted screening procedures.

TABLE OF RELATIVE RADIATION ACTIVITY Toxicity Radiation Studies Name and Formula of Compound, USAF No. and Approx. Dose X-ray Dose Change in Mortality Vehicle Used for Toxicity LD in in in ST in at 30 Days and Radiation Tests mgmJkgm. mgm./kgm. Roentgene Days After X-ray 3-nitro-4'-chloro- 15 10 700 0 9/10 salicylanilide 5 700 +2 10/10 5-nitro-4'-chlor0- 40 25 700 0 10/10 salicylanilide 10 700 +4 9/10 Finally, 3-nitrohalosalicylanilides have a marked, unexpected, unpredictable and unobvious greater toxicity (4 to 1) over the corresponding 5- nitrohalosalicylanilides when evaluated by the intraperitoneal route in rodents (small white rats), exhibiting an LD of approximately 35 mg./Kg in contrast with an 4. The 3-nitrohalosalicylanilide according to claim 2 aving the formula 3,929,879 7 8 5. The 3-nitrohalosalicylanilide according to claim 2 8. The 3-nitrohalosalicylanilide according to claim 2 having the formula having the formula N OH NO co NH c1 6. The 3-nitrohalosalicylanilide according to claim 2 co NH @Br having the formula NO OH 9. A 3-nitrohalosalicylanilide having the formula co NH @-Fl NO2\ /OH Cl 7. The 3-nitrohalosalicylanilide according to claim 2 g having the formula l 5 CO NH @-Cl NO2\/OH CO-NH@-I 

1. A 3-NITROHALOSALICYLANILIDE HAVING THE FORMULA
 2. A 3-nitrohalosalicylanilide having the formula
 3. The 3-nitrohalosalicylanilide according to claim 2 having the formula
 4. The 3-nitrohalosalicylanilide according to claim 2 having the formula
 5. The 3-nitrohalosalicylanilide according to claim 2 having the formula
 6. The 3-nitrohalosalicylanilide according to claim 2 having the formula
 7. The 3-nitrohalosalicylanilide according to claim 2 having the formula
 8. The 3-nitrohalosalicylanilide according to claim 2 having the formula
 9. A 3-nitrohalosalicylanilide having the formula 